The overall objective of this program project is to understand how macrophages become activated/deactivated for tumor cell killing. The group's efforts will be led by an established scientist in the field, who is also an experienced biomedical administrator, Dr. Stephen W. Russell. The objective of the first project leader, Dr. David C. Morrison, is to establish how LPS initiates activation. He will focus on the receptor proteins for LPS that he has discovered, as well as hydrophobic interactions between LPS and macrophage membranes that may contribute to initiation of the signal(s) for activation. Dr. Tsuneo Suzuki (project leader #2) will investigate the hypothesis that LPS binding to macrophages activates protein kinase C (PKC) by triggering phosphatidylinositol turnover as well as activation of the neutral intracellular proteinase, calpain, which then cleaves and activates PKC. Dr. Russell (project leader #3) will have as his group's goal the delineation of precisely how type I interferons affect activation. His emphasis will primarily be on how the induction and expression of cytolytic mechanisms are affected, as well as positive and negative autocrine/paracrine regulatory effects of macrophage- produced IFN. The associated regulatory mechanisms will be defined. Dr. Michael J. Parmely (project leader #4) and his group will focus on the role that TGF-beta has in regulating the activation of mouse macrophages. Specifically, he will characterize the production of latent and active forms of TGF-beta by mouse macrophages, determine how active TGF-beta affects the mediation of tumoricidal activity by activated macrophages, and ascertain the extent to which these regulatory effects are of autocrine origin. The Core Component, consisting of administrative support under the supervision of Dr. Russell, will be the means by which maximal integration and, therefore, synergism among the various projects is obtained. The Core Component's Research Program Coordinator will provide administrative support that is designed to make the projects function as integral parts of a whole, rather than as independent endeavors. Because of the natural complementarity of the projects and the essential, central functions that will be provided by the Core Component, it is hard to imagine how the group interactions and synergism that are sought as general goals of any program project will not be realized here.